1. Field of the Invention
This invention relates to a method for treating and preventing retinopathy and other small vessel disorders associated with diabetes.
2 . Description of the Prior Art
Diabetes mellitus causes retinopathy. Indeed, diabetes mellitus causes abnormal blood-ocular barrier permeability, which subsequently results in diabetic retinopathy. Nonproliferative phases of this condition are intraretinal, with primary pathogenic processes involving vascular leakage and vessel occlusion. Employing vitreous fluorophotometry, Cunha Vaz etal., Cunha Vaz, J. G., Faria de Abreu, J. R. , Campos, A. J. , Figo, G. M. , "Early Breakdown of the Blood Retinal Barrier in Diabetes," Br. J. Ophthalmol., 59, 649-56 (1975) , performed one of the earliest studies that indicated diabetic patients showed vitreal leakage of sodium fluorescein, whereas nondiabetic individuals did not. Since then, others have observed changes in blood-ocular barrier sodium fluorescein permeability in diabetic humans and rats. noting that these changes may occur before any ophthalmoscoscopic or angiographic signs of diabetic retinopathy are present, waltman, S. R., Oestrich, C., Krupin, T., Hanish, S., Ratzan. S., Santiago, J., Kilo, C., "Quantitative vitreous Fluorophotometry. A Sensitive Technique for Measuring Early Breakdown of the Bloodretinal Barrier in Young Diabetic Patients," Diabetes, 27, 85-7 (1970), Ishibashi, T., Tanaka, K., Taniguchi, Y., "Disruption of Blood-Retinal Barrier in Experimental Diabetic Rats: An Electron Microscopic Study," Exp. Eye. Res, 30, 401-10 (1980).
Causes of blood-ocular leakage in diabetics are still unresolved, although there is considerable agreement that hyperglycemia is an important contributing factor. Orlidie and Hollis, Orlidge, A., Hollis, T. M., "Aortic Endothelial and Smooth Muscle Histamine Metabolism in Experimental Diabetes," Arteriosclerosis, 2, 142-50 (1982), reported that aortic endothelial and smooth muscle cell histamine synthesis is increased in streptozotocin diabetic rats. This increase in histamine synthesis was normalized by insulin treatment, as well as by treatment with alpha hydrazinohistidine, a relatively specific inhibitor of histidine decarboxylase, Hollis, T. M., Gallik, S. G., Orlidge, A., Yost, J. C., "Aortic Endothelial and Smooth Muscle Histamine Metabolism. Relationship to Aortic 125I Albumin Accumulation in Experimental Diabetes," Arteriosclerosis, 3, 599-606 (1983), hyperglycemic rats treated ,with alphahydrazinohistidine also exhibited normal aortic albumin permeability characteristics in contrast to elevated permeability in diabetic rate not aiven this inhibitor. Plasma histamine concentrations are elevated in diabetic rats, Hollis, T. M., Kern, J. A., Enea, N. A., Cosgarea, A. J., "Changes in Plasma Histamine Concentration in the Streptozotocin Diabetic Rat," Exp. Mol. Pathol, 43, 90-6 (1985), as is retinal histamine synthesis, Carroll, W. C., Hollis, T. M., "Retinal Histamine Synthesis is Increased in the Streptozotocin Diabetic Rat, Invest Ophthalmol."Vis Sci, 29, 1201-04 (1988). Finally, chronic intravenous histamine infusion in nondiabetic rats raises their plasma histamine concentrations to those of diabetic animals, thereby increasing blood-ocular albumin leakage, Dull, R. O., Vergie, G. J., Hollis, T. M., "Effect of Chronic Histamine Infusion on the Permeability of the Blood Retinal Barrier," Fed. Proc. 45, 462 (1986).
It is further known that diabetes mellitus is responsible for other small vessel disorders in mammals. Such other small vessel complications arise in the kidney brain (stroke), heart (heart attack), feet (peripheral vascular disease), skin (skin necrosis), and nerves (peripheral neuropathy).
It is therefore an object of the present invention to provide a method for treating and preventing retinopathy.
It is a further object cf the present invention to provide a method for treating and preventing other small vessel complications which arise in connection with diabetes.
These and other objects are achieved through the application of a therapeutically effective amount of an antihistamine, or a pharmaceutically acceptable derivative thereof to a diabetic mammal which substantially prevents or minimizes the occurrence of retinopathy and other small vessel disorders which typically arise from diabetes.